Advancing the Development Pipeline for the Treatment of

United States Department of

Health & Human Services Office of the Assistant Secretary for Preparedness and Response

Advancing the Development Pipeline for the Treatment of Influenza

Melissa Willis, Ph.D. Chief, Influenza Therapeutics

Influenza Division BARDA

ASPR: Resilient People. Healthy Communities. A Nation Prepared. 2

Roadmap

• What is our goal? • Where have we

been? • Where are we

going? • Why now? • What strategies we

are pursuing to achieve the goal?


BARDA Influenza Antiviral Program

Program Goal “Reduce morbidity and mortality in all patient populations during an

influenza pandemic by supporting advanced development, evaluation, and approval of new influenza antiviral drugs”

• Mission established in the 2005 National Strategy for Pandemic Influenza, HHSPandemic Influenza Plan and the 2006 Implementation Plan for the NationalStrategy for Pandemic Influenza

• Initial stockpiling goal and advanced development projects• Stockpile total of 81M treatment courses of influenza antiviral drugs• Advanced development of new antiviral drugs

• New BARDA advanced development projects are focused on developing drugs toaddress critical unmet needs in treating severely ill, hospitalized patients and inpediatric populations

• Novel mechanisms of action• Combination therapy

Our total reliance on monotherapy with NAI’s has placed us at risk of no treatment options to address a potential NAI-resistant pandemic

ASPR: Resilient People. Healthy Communities. A Nation Prepared.

BARDA Influenza Therapeutics Program Line-Up

• Two large, full development programs for neuraminidase inhibitors• BioCryst—treatment of severely ill, hospitalized patients

• During 2009 pandemic, IV peramivir received the 1st EUA for an unapproved drug• Biota—long acting, single dose treatment

• Two smaller, targeted development programs for compounds with novelmechanisms of action

• Ansun—recombinant sialidase prevents viral attachment to cells• Romark—Broad spectrum antiviral targeting host pathways

FY07 FY08 FY10 FY11 FY12

BioCryst

FY13

Existing Completed/Ended

FY14 FY15 FY16 FY17 FY09

Biota

Ansun

Romark

= NDA Filing

4


Challenges and Gaps

• Expecting a single drug or class of drugs to treat all stages of influenza infection and all populations might be a stretch

• Historically driven by a limited pipeline

• Leaves gaps in our preparedness: ─ Severely ill, hospitalized

influenza patients ─ More effective treatment

options, suitable for all populations including pediatrics


Influenza Antiviral Landscape in 2006


Influenza Antiviral Landscape 2014

NA Inhibitors

Other Viral Targets

M-2 Blockers

Flumadine (Rimantadine)

Inhaled

IV

Oral

Other

VIS410 mAb-HA Grp1+2

CR6261 mAb-HA Grp1

CT-P27 mAb-HA Grp1+2

Anti-Flu A mAb-HA Grp1+2

Genentech TCN-032

mAb-M2e Grp 1+2

Anti Influenza IVIG

2D1 mAb-HA

Hyperimmune IVIG

University of Hong Kong

Anti-HA

Anti-NA

CR8020 mAb-HA Grp2

Fabenflu Equine pAb

(H5N1)

CR9114 mAb-HAGrp1+2

Antibodies FI6v3 mAb-HA Grp1+2

CF-404

Tamiphosphor

FluCide TM Endonuclease TCAD Combo

A06 MAb-HA

Virazole (ribavirun) Flufirvitide-3 Cap Snatch/

T-705 (Pol in)

RapiActa

inhibitor Matrix AVI-7100

Pre-Clinical Phase 1 Phase 3 Market Approved Phase 2

VX-787

Peramivir

Zanamivir

Relenza

Tamiflu Inavir

Symmetrel

Laninamivirr

(Amantadine)

http://www.gene.com/





Influenza Antiviral Landscape 2014

Inhaled

IV

Oral

Other

Pre-Clinical Phase 1 Phase 2 Phase 3 Market Approved

Host Targets

Nitazoxanide

CC10 protein Surfaxin

Homspera (Neurokinin-1) PUR003

Alferon LDO

NTHi (pro-imf)

GP1002

Gemmus

Pharma

Eritoran TLR4

Antagonist

Archaeon Acetyl-salicylic

acid (ASA) Nf-κB Inhibitor

Fludase

Ansun BioPharma

EV-077






Where Are We Going?

• We need new options to address pandemic threats ─ Therapies with a wider treatment window

• >48h of symptom onset ─ Therapies that have a reduced threat of resistance

• Novel MOA including host directed therapies • Combination therapies

─ Options for special populations • Alternative formulations (IV for hospitalized) • Approved drugs for severely ill, hospitalized patients • Treatment options and formulations for pediatric patients

─ Broad spectrum activity for influenza and/or other emerging diseases suitable for community use


Shifting Focus. Why now?

• Emergence of antiviral resistance (adamantanes and NAI)

• Lack of drugs to treat late-stage disease – need a wider treatment window for the severely ill hospitalized population

“A clear advance would be the ability to treat later in the course of disease.” Arnold Monto

• Discovery and development of broadly neutralizing antibodies

Antiviral Therapy 2010; 15:853-859


Broad Spectrum Neutralizing Monoclonal Antibodies

• Target the HA stalk ─ Highly conserved ─ Novel target ─ Broad spectrum – Group 1 and

2, Influenza B • Unique properties

─ Extended treatment window ─ Long half life resulting in single

dose administration ─ Large binding surface reducing

likelihood for resistance


Influenza HA and Stalk mAbs

HA1

Head

Stalk

mAb

mAb

HA2


Strategies to Address Unmet Needs

Critical unmet medical needs: Severely ill, hospitalized influenza patients More effective treatment options, suitable for all populations

• If the drug is a monoclonal antibody, then: ─ Broad spectrum = one or two mAbs cover all subgroups of Influenza A ─ IV formulation amenable to treatment of the severely ill ─ Expanded treatment window = must be effective more than 48 hours

after symptom onset

• If the drug is a small molecule, then: ─ Needs to work better than neuraminidase inhibitors (NAIs) ─ Inhibits all Influenza A strains tested ─ Expanded treatment window beyond 48 hours ─ Suitable for combination therapy with existing NAI ─ Oral and IV formulations


Strategies to Address Unmet Needs (2)

Critical unmet medical needs: Severely ill, hospitalized influenza patients More effective treatment options, suitable for all populations

• If the drug is a host directed therapy, then: ─ Can have direct antiviral activity ─ Restore immunological homeostasis in an influenza infection ─ Demonstrate improved outcomes in the severely ill, hospitalized

population when given alone or in combination with SOC antivirals ─ Expanded treatment window = must be effective more than 48 hours

after symptom onset


Partnership Opportunities with BARDA

• Broad Agency Announcement (BAA) https://www.medicalcountermeasures.gov/newsroom/2013/now-open-broad-agency-announcements.aspx

• Request for Proposal (RFP) FY2015 ─ RFP with funding to make base awards for promising programs


Questions?

TEAM Karl Erlandson Kevin Gilligan Alan Goldberg Alan Jackson John Tegeris Mike Wathen

[email protected]

Documents

Advancing the Development Pipeline for the Treatment of